The retina is both a sensory organ and a self-sustained neural circadian clock. As the primary sensory organ for vision, the retina performs the initial steps of transduction and encoding of physical light stimuli into neural signals, and then transmits visual and photic information to the rest of the brain via the optic nerve. The intrinsic retinal circadian clock shapes overall retinal sensory function into high acuity "day" and high sensitivity "night" states by modulating retinal neurons and reconfiguring retinal circuits through rhythmic gene expression and rhythmic of release of modulatory neurotransmitters such as dopamine and melatonin. Although the retinal circadian clock exerts extensive influence over retinal physiology and metabolism, the underlying cellular and molecular mechanisms of the retinal circadian clock are not well understood. The long-term goal of the research proposed here is to elucidate the fundamental mechanisms of the mammalian retinal circadian clock and its control of retinal sensory function. For the upcoming award period we propose to examine the functional role of specific circadian clock genes and cell populations in the retinal circadian clock, as well as the mechanisms by which the retinal clock modulates retinal sensitivity. Specifically, we propose to examine the following issues: Specific Aim I: Molecular Organization of the Retinal Circadian Clock. Using mouse lines in which the core circadian clock genes Per1, Per2, Cry1, Cry2, Clock and NPAS2 are knocked out we will test the functional role of each of these genes in the mouse retinal circadian clock. Specific Aim II. Cellular Organization of the Retinal Circadian Clock. Using single-cell luminescence imaging and cell- specific manipulation of molecular circadian clock function via mouse lines carrying floxed alleles of the core clock gene Bmal1 and cell-specific expression of Cre recombinase, we will seek to determine which cell populations in the retina are circadian pacemakers. Specific Aim III. Circadian Clock Control of Retinal Function. Using molecular genetic approaches, we will test which cells and transmitter pathways are critical for: (1) circadian control of retinal sensitivity using the ERG, and (2) light entrainment of the retinal clock. Completion of these aims will provide insight into the underlying mechanisms by which visual function and sensitivity is modulated according to time of day in many organisms, including humans. These findings will be fundamental for understanding normal retinal function, the retina as a model biological clock system, and contribute to our understanding of clinically relevant circadian and dopaminergic retinal mechanisms associated with photoreceptor degeneration and myopia. PUBLIC HEALTH RELEVANCE: Our vision is different at different times of day because our retina works differently at different times of day. These functional daily rhythms are not simple responses to the daily light-dark cycle, but, as demonstrated by their persistence in constant darkness, they are the overt expression of an endogenous, self-sustained circadian clock in the retina that drives many rhythms in retinal physiology and metabolism. The retinal circadian clock adjusts retinal function, biasing it appropriately for day or night vision. In addition, the retinal clock imparts differential vulnerability to retinal light damage at different times of day, is altered in the blinding disease retinitis pigmentosa, and influences macular edema and the development of myopia. Increased understanding of the retinal circadian clock is important to understanding human vision and its preservation and to elucidating the mechanisms of this model neural circadian pacemaker.